Food and Drug Administration reviewers think Lamictal XR may be effective as a monotherapy for partial seizures, but they identified problems with the novel historical control trial design, including issues with U.S. versus ex-U.S. populations, that may have prevented a definitive conclusion.

Members of the Peripheral and Central Nervous System Drugs Advisory Committee seem likely to spend most of their March 10 meeting considering questions about the methodology used in the Lamictal XR (lamotrigine extended-release tablets) trial, before deciding whether it is effective as a monotherapy in patients aged 13 years and older.

GlaxoSmithKline compared its new treatment group with data from control groups in eight monotherapy studies of anticonvulsants previously completed. The historical data and statistical method was outlined in a white paper developed by researchers from the University of Pennsylvania.

A historical control study design has never been accepted by the Division of Neurology Products, even if the goal was to show superiority, because of interpretation difficulties, according to FDA briefing documents.

The FDA is actually fairly confident that Lamictal XR could be an effective monotherapy, in part because it already is approved as an adjunctive therapy and its immediate-release cousin has been shown to be effective as a monotherapy, division director Dr. Russell Katz said in the briefing memo.

The primary difficulty with the design is a "lack of assurance that the patients in the control group and the treated group are ‘identical,’ " Dr. Katz said in the briefing.

Reviewers said in the clinical and statistical review that they were not convinced of the generalizability of the drug’s non-U.S. data to historical U.S. patients. The agency found several issues in which the control population was not comparable to the treatment population, yet reviewers still indicated that, after adjustments, there was evidence of Lamictal XR’s efficacy.

GSK conducted its pivotal LAM30055 study of Lamictal XR in seven countries, including South American and Eastern European states, as well as the United States. The control group contained nearly all U.S. patients, while the treatment group contained about 25% U.S. patients, a group not designed to stand alone in an analysis with the historical controls. Reviewers said it was a problem because a higher percentage of U.S. patients met escape criteria – that is, they did not see reduced symptoms on study drug – than non-U.S. patients.

Reviewers also cited a time difference in comparing the control and treatment groups.

"The span of the pseudoplacebo population ranges from approximately 1992 to 2001," reviewers said in the briefing document. "In the oldest white paper study the pseudoplacebo patients will be almost a generation older than the study population."

Multiple Escapes and Other Study Problems

The control group population also allowed patients to use up to two background antiepileptic drugs, while the treatment group was allowed only one stable background antiepileptic drug. The agency said in its briefing that patients on multiple antiepileptic drugs can be more prone to escape events. Those on one stable monotherapy also have a lower chance of nonresponse to the study drug, the agency said.

Still, after adjusting to look at only those control-group patients on one antiepileptic drug, the agency concluded Lamictal XR was superior.

There also were concerns about underreporting escapes in the trial. After errors were found, GSK retrained study site monitors and other personnel and performed a post-hoc analysis that corrected some of the issues.

Escape events were grouped into four categories covering various incidents of increased or worsening seizures. Reviewers found that the trial had no incidents reported of criterion No. 4, which was clinically significant prolongation of generalized tonic-clonic seizures. They said its absence made comparisons with the control more difficult.

"It was uncertain how to adequately assess the potential bias due to under-reporting criterion No. 4 events," reviewers said in the briefing.

Ethical Issues Will Be Addressed First

GSK submitted its supplemental new drug application for monotherapy treatment of partial seizures in late March 2010. The user fee date was extended from the end of January to April 30 after the FDA requested additional analyses and datasets.

One of the primary reasons for the questions to the advisory committee is the ethical dilemma of using a placebo-controlled monotherapy study in patients with partial seizures. If the committee decides that design is ethical, it will skip the next question asking whether the historical control statistical approach is acceptable. In all, most of the remaining questions, which concern the study methodology, including use of domestic and foreign data, could be rendered moot.

The final question deals with the effectiveness of Lamictal XR as a monotherapy.

The FDA has been considering the historical controls question for several years and its decision could affect several other drugs in late-stage trials seeking similar monotherapy indications.

Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.

Lamictal XR Study Design Problems Identified